9-[4-(3-chloro-2-fluoro-phenylamino-7-methoxy-quinazoline-6-yloxy]-1,4-diaza-spiro[5.5]undecane-5-one dimaleate, use thereof as a medicament and method for the production thereof

ABSTRACT

The present invention relates to a compound of formula (I), 
                         
which has valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by tyrosine kinases, processes for stereoselectively preparing these compounds, particularly pharmaceutical formulations suitable for inhalation and their use for the treatment of diseases, particularly tumoral diseases, benign prostatic hyperplasia and diseases of the lungs and airways.

The present invention relates to the compound of formula (I),

which has valuable pharmacological properties, particularly aninhibiting effect on signal transduction mediated by tyrosine kinases,processes for stereoselectively preparing this compound, particularlypharmaceutical formulations suitable for inhalation and their use forthe treatment of diseases, particularly tumoral diseases, benignprostatic hyperplasia and diseases of the lungs and airways.

BACKGROUND TO THE INVENTION

Quinazoline derivatives are known from the prior art as activesubstances for example for the treatment of tumoral diseases and alsodiseases of the lungs and airways. Processes for preparing quinazolinederivatives are described in WO03082290 and WO07068552. WO2009098061discloses the base (compound (II)) of the dimaleate salt according tothe invention (compound (I)).

The aim of the present invention is to provide a salt of9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-onewhich by virtue of its pharmaceutical efficacy as a tyrosine-kinaseinhibitor is suitable for use in the therapeutic field, i.e. for thetreatment of pathophysiological processes that are caused by thehyperfunction of tyrosine-kinases.

A further aim is to provide a compound that meets the requirements forphysical and chemical stability and other properties, such as forexample crystalline stability, the absence of polymorphism and lowhygroscopicity, particularly with regard to the absence of polymorphism,that are imposed on an active substance of a medicament. Another aim ofthe present invention is to provide a stereoselective process forpreparing the compound according to the invention.

DESCRIPTION OF THE DRAWINGS

FIG. 1: X-ray powder diagram of compound (I)

FIG. 2: DSC/TG schemes of compound (I)

FIG. 3: Sorption isotherms of compound (I): a.) kinetic plot, b.)isothermic plot

DETAILED DESCRIPTION OF THE INVENTION

The present invention solves the above-mentioned problems by providingthe compound of formula (I) that is suitable in particular for oraladministration, which is highly crystalline, has low hygroscopicity andlow polymorphism, the pharmaceutical formulation thereof and the methodof synthesis described hereinafter. By crystalline stability is meant,within the scope of the present invention, that X-ray powder diagrams ofthe compound of formula (I) have sharp reflections with high intensityup to the upper 2 θ range, preferably up to 20-40° 2 θ.

By low hygroscopicity is meant, within the scope of the presentinvention, that in sorption experiments on the compound of formula (I) awater uptake of less than 1% is observed in the humidity range of 10-90%investigated.

By low polymorphism is meant, within the scope of the present invention,that after recrystallization from different solvents of the compound offormula (I) a maximum of 5 other crystal modifications, preferably amaximum of 3 other crystal modifications, particularly preferably noother crystal modifications are obtained.

The invention relates to a compound of formula (I)

optionally in the form of the tautomers, solvates or hydrates thereof.

A crystalline compound of formula (I) is preferred wherein reflectionsoccur in the X-ray powder diagram with d_(hkl) values of 7.11, 5.77,4.69, 4.36, 4.15, 3.85 and 3.61 Å.

The invention further relates to the above-mentioned compound for use asa medicament, preferably for the treatment of inflammatory or allergicdiseases of the airways, particularly preferably for the treatment ofchronic obstructive bronchitis (COPD) and/or chronic bronchitis.

The compound of formula (I) is useful for treating diseases, preferablyselected from among acute bronchitis, bronchitis caused by bacterial orviral infection or fungi or helminths, allergic bronchitis, toxicbronchitis, asthma (intrinsic or allergic), paediatric asthma,bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis,chronic sinusitis, cystic fibrosis or mucoviscidosis,alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitiallung diseases, alveolitis, hyperreactive airways, nasal polyps,pulmonary oedema, pneumonitis of different origins, e.g.radiation-induced or caused by aspiration or infectious pneumonitis,collagenoses such as lupus erythematodes, systemic scleroderma,sarcoidosis and Boeck's disease, and for treating complications inasthma and COPD triggered by viral, bacterial or other causes, fortreating viral or bacterial infections of the airways or lungs.

It is also preferred to use the compound of formula (I) in cases ofinflammatory or allergic complaints in which autoimmune reactions areinvolved.

It is also preferred to use the compounds of formula (I) in cases of adisease in the form of benign or malignant tumours.

The invention further relates to a process for the stereoselectivepreparation of the compound of formula (I), optionally in the form ofthe tautomers, solvates or hydrates thereof:

-   -   the process comprising reaction steps (A) to (M), wherein    -   (A) denotes the reaction of        1,4-cyclohexanedione-mono-ethyleneketal to form a compound of        formula (1)

-   -   (B) is the reaction of a compound of formula (1) to form the        compound of formula (2)

-   -   (C) is the reaction of a compound of formula (2) to form the        compound of formula (3)

-   -   (D) is the reaction of a compound of formula (3) with a        protective group reagent to form the compound of formula (4)

-   -   (E) is the reduction of a compound of formula (4) to form the        compound of formula (5)

-   -   (F) is the reaction of a compound of formula (5) to form a        compound of formula (6)

-   -   (G) is the reaction of a compound of formula (6) with a compound        of formula (13) to form a compound of formula (7)

-   -   (H) is the reaction of a compound of formula (7) to form a        compound of formula (8a) or its tautomeric form (8b),

-   -   (I) is the chlorination of the compound of formula (8a) or (8b)        to form a compound of formula (9)

-   -   (J)+(K) are the reaction of the compound of formula (9) with        3-chloro-2-fluoraniline and the cleaving of a protective group        to form a compound of formula (11) or (11A)

-   -   (L) is the cleaving of another protective group to form the        compound of formula (II)

-   -   (M) is the reaction of the compound of formula (II) with maleic        acid to form a compound of formula (I), optionally in the form        of the tautomers, solvates or hydrates thereof,

-   -   while process steps (A) to (M) take place successively in the        sequence indicated.

The invention further relates to a process for the stereoselectivepreparation of the compound of formula (I), optionally in the form ofthe tautomers, solvates or hydrates thereof, comprising process steps(A) to (M),

wherein process steps (J+K) are replaced by steps (N+O), where

-   -   (N+O) is the cleaving of a protective group of the compound of        formula (9) to form the compound of formula (12) and subsequent        reaction with 3-chloro-2-fluoraniline to form the compound of        formula (11) or (11A)

-   In a preferred process for the stereoselective preparation of a    compound of formula (I), the process consists of process steps (I),    (J), (K), (L), and (M) or of process steps (I), (N), (O), (L) and    (M), while process steps (I) to (M) in each case take place    successively in the order indicated.-   Another preferred process for the stereoselective preparation of a    compound of formula (II) is characterized in that the process    consists of process steps (I), (J), (K) and (L), or of process steps    (I), (N), (O) and (L), while process steps (I) to (L) in each case    take place successively in the order indicated.

Particularly preferred is process step (G).

Also particularly preferred is process step (I).

-   The invention further relates to the intermediate of formula (6),    optionally in the form of the tautomers, solvates or hydrates    thereof.-   The invention further relates to the intermediate of formula (7),    optionally in the form of the tautomers, solvates or hydrates    thereof.-   The invention further relates to the intermediate of formula (8),    optionally in the form of the tautomers, solvates or hydrates    thereof.-   The invention further relates to the intermediate of formula (9),    optionally in the form of the tautomers, solvates or hydrates    thereof.-   The invention further relates to the intermediate of formula (11) or    (11A), optionally in the form of the tautomers, solvates or hydrates    thereof.

The invention further relates to a pharmaceutical composition containinga compound of formula (I). An orally administered pharmaceuticalcomposition containing a compound of formula (I) is preferred.

-   In another aspect the invention relates to medicament combinations    which contain, in addition to a compound of formula (I) according to    claim 1, as a further active substance, one or more compounds    selected from among the categories of the betamimetics,    anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-receptor    antagonists, LTB4-receptor antagonists, inhibitors of MAP kinases,    bradykinin receptor antagonists, endothelin receptor antagonists,    CXCR1 and/or CXCR2 receptor antagonists, and antitussives, or double    or triple combinations thereof.

In process steps A, C to L and N alternative reagents may be used, whichare selected from among the reagents listed below:

In Process Step

-   A: in addition to ethylenediamine and chloroform:    -   preferably benzyltriethylammonium chloride/NaOH,        tetrabutylammonium chloride/KOH, benzyltriethylammonium        chloride/KOH,_tetrabutylammonium chloride/NaOH, particularly        preferably benzyltriethylammonium chloride/NaOH;-   C: preferably alkoxide bases selected from among NaO^(t)Bu, KO^(t)Bu    and NaOEt, carbonate bases selected from among Cs₂CO₃, K₂CO₃, Li₂CO₃    and Na₂CO₃, particularly preferably sodium methoxide;-   D: in addition to di-tert-butyldicarbonate and DMAP    (4-(dimethylamino)-pyridine): preferably K₂CO₃, Cs₂CO₃, Li₂CO₃ and    Na₂CO₃, particularly preferably K₂CO₃;-   E: preferably NaBH₄ and LiBH₄, particularly preferably NaBH₄,-   F: in addition to trifluoroacetic anhydride:    -   as base preferably triethylamine, Hünig base, N-methylmorpholine        and N,N-diethylaniline, particularly preferably triethylamine;-   G: in addition to 3-benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one:    -   preferably triphenylphosphine/diisopropyl azodicarboxylate,        triphenylphosphine/diethyl azodicarboxylate,        tributylphosphine/1,1′-(azodicarbonyl)dipiperidine, particularly        preferably triphenylphosphine/diisopropyl azodicarboxylate;-   H: catalysts, preferably selected from among Pd/C and Pd(OH)₂,    particularly preferably Pd/C;-   I: preferably N-chlorosuccinimide/triphenylphosphane (in    combination), oxalyl chloride, thionyl chloride, phosphorus    oxychloride, phosphorus pentachloride, carbon    tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane and    P,P-dichlorophenylphosphine oxide, particularly preferably    N-chlorosuccinimide/triphenylphosphane (in combination);-   J+K: in addition to 3-chloro-2-fluooraniline:    -   preferably HCl, methanesulphonic acid, ethanesulphonic acid,        p-toluenesulphonic acid and HBr, particularly preferably HCl;-   L: preferably ethanolamine, ammonia and Ba(OH)₂, particularly    preferably ethanolamine;-   I+N: preferably N-chlorosuccinimide/triphenylphosphane (in    combination), HCl, oxalyl chloride, thionyl chloride, phosphorus    oxychloride, phosphorus pentachloride, carbon    tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane,    P,P-dichlorophenylphosphine oxide, methanesulphonic acid,    ethanesulphonic acid, p-toluenesulphonic acid and HBr, particularly    preferably N-chlorosuccinimide/triphenylphosphane (in combination)    and HCl.

The use of the following solvents selected from the group specified ineach case is preferred in the process steps described above:

In Process Step

-   A: CH₂Cl₂, CHCl₃, THF (tetrahydrofuran) and dioxane;-   B: HOAc, dioxane, H₂O and aqueous solutions of the following    solvents selected from among EtOH, THF, iPrOH, MeOH, NMP    (N-methyl-2-pyrrolidone) and DMF (dimethylformamide);-   C: ACN(CH₃CN), EtOH, MeOH, iPrOH, H₂O, THF and NMP;-   D: ACN, EtOH and NMP;-   E: H₂O, MeOH, EtOH, THF and dioxane;-   F: Me-THF, THF, toluene, CH₂Cl₂ and dioxane;-   G: THF, NMP, dioxane, DMF and CH₂Cl₂;-   H: iPrOH, dioxane, EtOH, MeOH, THF and NMP;-   I: dioxane/ACN and THF/dioxane;-   J: ACN, dioxane, THF and EtOH;-   K: ACN, dioxane, THF and EtOH;-   L: EtOH, MeOH, iPrOH and dioxane;-   M: EtOH, MeOH and H₂O;-   N: dioxane/ACN and THF/dioxane-   O: EtOH, n-PrOH, dioxane and NMP

The process steps described above are preferably carried out in thefollowing temperature ranges:

In Process Step:

-   A: preferably −15 to 40° C., particularly preferably 0 to 20° C.;-   B: preferably 0 to 100° C., particularly preferably 75 to 100° C.;-   C: preferably 0 to 65° C., particularly preferably 15 to 30° C.;-   D: preferably 10 to 80° C., particularly preferably 15 to 35° C.;-   E: preferably 0 to 40° C., particularly preferably 0 to 15° C.;-   F: preferably −10 to 60° C., particularly preferably 0 to 35° C.;-   G: preferably 10 to 65° C., particularly preferably 45 to 60° C.;-   H: preferably 20 to 85° C., particularly preferably 70 to 85° C.;-   I: preferably 20 to 100° C., particularly preferably 70 to 95° C.;-   J: preferably 20 to 100° C., particularly preferably 50 to 85° C.;-   K: preferably 20 to 100° C., particularly preferably 50 to 85° C.;-   L: preferably 50 to 80° C., particularly preferably 70 to 80° C.;-   M: preferably 0 to 75° C., particularly preferably 0 to 70° C.-   N: preferably 20 to 100° C., particularly preferably 50 to 85° C.;-   O: preferably 50 to 100° C., particularly preferably 70 to 80° C.;

Preferably, protective groups selected from among benzyl, Cbz,trifluoracetyl and Boc, particularly trifluoracetyl and Boc, are used.

The abbreviation Boc used in the above formulae denotes tertiary butylcarbamate and Cbz denotes benzyloxycarbonyl.

Scheme 1 illustrates the synthesis according to the invention. All thecompounds are shown in the form of their bases.

The following Examples serve to illustrate the processes carried out byway of example for preparing the compound of formula (I). These Examplesare to be understood as being an illustration of the invention, withoutlimiting it to their subject-matter.

Example 1 1,4-dioxa-9,12-diaza-dispiro[4.2.5.2]pentadecan-13-one

Process Step A

15.1 kg of 50% sodium hydroxide solution are added dropwise at 5° C. toa mixture of 437 g benzyltriethylammonium chloride and 2700 mlethylenediamine in 19.2 L dichloromethane. Then a solution of 6000 g of1,4-cyclohexanedione-mono-ethyleneketal and 6100 g chloroform in 4.8 Ldichloromethane within the next 4.5 h is added dropwise at 5-15° C. Thedropping funnel is rinsed with 3 L dichloromethane. After 15 h, 18 Lwater and 39 L dichloromethane are added at 15-25° C. The phases areseparated and the aqueous phase is extracted with 20 L dichloromethane.The combined organic phases are concentrated by distillation. After 72 Lsolvent have been distilled off, 48 L isopropanol are added to thesuspension and then a further 30 L solvent are distilled off. Aftercooling to 3° C. the precipitate is filtered off and washed twice with7.5 L cold isopropanol. After drying at 50° C. in vacuo, 6144 g ofproduct is obtained.

Mass spectrum (ESL): m/z=227 [M+H]⁺

Example 2 1,4-diaza-spiro[5.5]undecane-5,9-dione

Process Step B

14.5 kg of 4M HCl in dioxane are added dropwise within 15 min to 6085 g1,4-dioxa-9,12-diaza-dispiro[4.2.5.2]pentadecan-13-one in 25 kg aceticacid at 80-100° C. The dropping funnel is rinsed with 3 kg acetic acid.After 140 min the suspension is cooled to 20° C. After 2 h theprecipitate is filtered off and washed twice with 12 L dioxane. Afterdrying at 60° C. in vacuo, 5333 g of product is obtained as thehydrochloride.

Mass spectrum (ESI⁺): m/z=183 [M+H]⁺

Process Step C

5200 g of 1,4-diaza-spiro[5.5]undecane-5,9-dione hydrochloride in 52 Lacetonitrile are combined with 4370 ml 30% sodium methoxide solution inmethanol at RT within 3 h. The dropping funnel is rinsed with 1 Lmethanol. 250 g sodium carbonate are added and the mixture is stirredfor 16 h. 30 L solvent are distilled off and after the addition of 20 Lacetonitrile the suspension is filtered. The filter cake is washed with10 L acetonitrile. 22 L solvent are distilled off from the filtrate andthe residue that contains the product is further reacted directly in thenext step.

Example 3 tert-butyl5,9-dioxo-1,4-diaza-spiro[5.5]undecane-4-carboxylate

Process Step D

6573 g potassium carbonate and 145 g 4-(dimethylamino)-pyridine areadded to the residue from the previous mixture which contains the1,4-diaza-spiro[5.5]undecane-5,9-dione. Then within 30 min 6487 gdi-tert-butyldicarbonate in 8 L acetonitrile is added dropwise. Thedropping funnel is rinsed with 2 L acetonitrile. After 100 min themixture is added to 20 L water at 10° C. It is rinsed with 2 L water, 5L acetonitrile and 16 L toluene. After phase separation the organicphase is combined with 10 L toluene. 55 L solvent are distilled off.After the addition of 30 L methylcyclohexane and 10 L toluene themixture is inoculated with product and the suspension is stirred for 14h at 20-30° C. 20 L methylcyclohexane are added and the mixture iscooled to −5° C. After 2.5 h the precipitate is filtered off and washedwith 10 L methylcyclohexane. After drying at 50° C. in vacuo, 5160 g ofproduct is obtained.

Mass spectrum (ESL): m/z=283 [M+H]+

Example 4 tert-butyl(cis)-9-hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-4-carboxylate

Process Step E

201 g sodium borohydride in 5 L water are added dropwise at 3° C. within17 min to a mixture of 5000 g of tert-butyl5,9-dioxo-1,4-diaza-spiro[5.5]undecane-4-carboxylate in 35 L water. Thedropping funnel is rinsed with 1.4 L water. After 15 min, 30 Lmethyl-tetrahydrofuran are added. After the addition of 10 L of sat.potassium carbonate solution the phases are separated and the aqueousphase is extracted with 20 L methyl-tetrahydrofuran. The combinedorganic phases are washed with 1 L sat. saline solution. The organicphase is separated off and diluted with 27.5 L methyl-tetrahydrofuran.55 L solvent are distilled off. Then 15 L methyl-tetrahydrofuran areadded and 15 L solvent are distilled off. Then 20 Lmethyl-tetrahydrofuran are added and 20 L solvent are distilled off.Then 20 L methyl-tetrahydrofuran are added and 20 L solvent aredistilled off. The residue which contains the product is further reacteddirectly in the next step.

Mass spectrum (ESI⁺): m/z=285 [M+H]⁺

Example 5 tert-butyl(cis)-9-hydroxy-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate

Process Step F

11.1 L triethylamine are added to the organic phase from the previousmixture. Then 5170 ml trifluoroacetic anhydride are added dropwisewithin 30 min at 3-25° C. After 15 min 12.4 L methanol are added. After1 h, 30 L solvent are distilled off in vacuo. Then 15.3 L methanol areadded and 8 L of solvent are distilled off in vacuo. 12.4 L methanol areadded and 35 L water are added dropwise at 1-10° C. within 50 min. After1 h at 2° C. the precipitate is centrifuged off and washed with 10 L ofa 2:1 mixture of water and methanol and then again washed with 10 Lwater. After drying at 55° C. in the circulating air dryer 5299 g ofproduct is obtained as a cis/trans mixture.

This crude product is suspended in 70 L toluene. Then 500 ml solvent aredistilled off and then 10 L toluene are added. The solution is cooledand at 52° C. it is inoculated with product. After 3 h at 1° C. theprecipitate is centrifuged off and washed with 8 L cold toluene. Afterdrying at 55° C. in vacuo 4398 g of product is obtained, which stillcontains approx. 4% trans product.

Mass spectrum (ESI⁺): m/z=381 [M+H]⁺

Example 6 tert-butyl(trans)-9-(3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate

Process Step G

2471 ml diisopropyl azodicarboxylate is added dropwise, within 100 min,to a mixture of 3500 g tert-butyl(cis)-9-hydroxy-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate,2362 g 3-benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one and 3292 gtriphenylphosphine in 45 L tetrahydrofuran at 50-55° C. The droppingfunnel is rinsed with 4 L tetrahydrofuran and 30 L solvent are distilledoff in vacuo. Then, during the continuous addition of 60 L ethanol, afurther 30 L solvent are distilled off at normal pressure. It isinoculated with product and left to cool slowly to RT. After 19 h, theprecipitate is filtered off and washed with 15 L ethanol. After dryingat 50° C. in vacuo, 4710 g of product is obtained.

Mass spectrum (ESI⁺): m/z=645 [M+H]⁺

Example 7 tert-butyl(trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate

Process Step H

470 g palladium (10%) on charcoal are added to a mixture of 4700 gtert-butyl(trans)-9-(3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylatein 33 L isopropanol and 33 L dioxane. After 4 h hydrogenation at 80° C.the mixture is filtered at 60° C. and washed with a mixture of 10 Lisopropanol and 10 L dioxane. 58 L solvent are distilled off from thefiltrate in vacuo and 32 L tert-butylmethylether are added. After 2 h at0-5° C. the precipitate is filtered off and washed with 15 Ltert-butylmethylether. After drying at 50° C. in vacuo 4153 g of productis obtained.

Mass spectrum (ESI⁺): m/z=555 [M+H]⁺

Example 8 tert-butyl(trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate

Process Step I

1590 g N-chlorosuccinimide in 20 L acetonitrile are added to a mixtureof 5500 g tert-butyl(trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylateand 3122 g triphenylphosphine in 24 L dioxane at 60° C. within oneminute. The dropping funnel is rinsed with 4 L acetonitrile and themixture is heated to 80-90° C. for 30 min. The mixture containing theproduct is used directly in the next step.

Example 9 tert-butyl(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate

(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-onehydrochloride

Process Step J+K

After 20 min at 50-60° C. 1733 g 3-chloro-2-fluoraniline are added tothe mixture. The dropping funnel is rinsed with 2 L acetonitrile. Then7.8 kg 4 M hydrochloric acid in dioxane are added and the mixture isstirred for 45 min at 55-80° C. After cooling to 1° C. the precipitateis filtered off and washed with 10 L ethanol. The precipitate issuspended in 40 L ethanol and combined with 290 g3-chloro-2-fluoroaniline. The suspension is stirred for 45 min at 70-80°C. and then for 13 h at RT. The precipitate is filtered off and washedwith 10 L ethanol. After drying at 60° C. in vacuo 4853 g of product isobtained as the hydrochloride.

Mass spectrum (ESI⁺): m/z=582 [M+H]⁺

or:

Process Step O

A mixture of 3.42 g(trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-oneand 1.25 g 3-chloro-2-fluoroaniline in 40 ml of ethanol is heated to 80°C. for 2 h. After the suspension has been cooled to 20° C. and stirredfor 16 h the precipitate is filtered off and washed with 10 mL ethanoland 10 mL tert-butylmethylether. After drying at 100° C. in vacuo, 3.28g of product is obtained.

Mass spectrum (ESI⁺): m/z=582 [M+H]⁺

Example 10(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one

Process Step L

A mixture of 4700 g(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-oneand 5150 g ethanolamine in 47 L ethanol is heated to 75-80° C. for 17 h.After the suspension has been cooled to 20° C. the precipitate isfiltered off and washed with 15 L ethanol. After drying at 60° C. invacuo, 3776 g of product is obtained as the mono-ethanol solvate.

Mass spectrum (ESI⁺): m/z=486 [M+H]⁺

1H NMR (400 MHz, DMSO): 9.60 (1H, s); 8.37 (1H, s); 7.82 (1H, s);7.44-7.55 (2H, m), 7.37 (1H, s); 7.28 (1H, t); 7.22 (1H, s); 4.63-4.69(1H, m); 4.33 (1H, t); 3.96 (3H, s); 3.41-3.49 (2H, m); 3.11-3.16 (2H,m); 2.82-2.87 (2H, m); 2.30 (1H, s); 2.14-2.23 (2H, m); 1.84-1.97 (4H,m); 1.44-1.51 (2H, m); 1.06 (3H, t).

Example 11(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-onedimaleic acid compound

Process Step M

A solution of 1680 g maleic acid in 7 L ethanol and 7 L water is addedat 77° C. to 3500 g(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-onemono-ethanol solvate in 18 L of ethanol. The dropping funnel is rinsedwith 3 L ethanol. The solution is inoculated with product at 66° C. andafter 5 min 35 L ethanol are added dropwise to the suspension. Thesuspension is cooled to 20° and stirred for 1 h at this temperature.Then it is cooled to 1° C. and stirred for 16 h at this temperature. Theprecipitate is filtered off and washed twice with 10 L ethanol. Afterdrying at 60° C. in vacuo, 4362 g of product is obtained.

Mass spectrum (ESI⁺): m/z=486 [M+H]⁺

1H NMR (400 MHz, DMSO): 8.50 (1H, s); 8.24 (1H, s); 7.93 (1H, s);7.50-7.57 (2H, m), 7.29-7.35 (1H, m); 7.27 (1H, s); 6.15 (4H, s);4.65-4.71 (1H, m); 3.98 (3H, s); 3.45-3.51 (2H, m); 3.39-3.44 (2H, m);2.38-2.48 (2H, m); 2.06-2.15 (2H, m); 1.83-2.02 (4H, m).

Example 12(trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-one

Process step I+N

19.6 g N-chlorosuccinimide in 240 mL acetonitrile are added at 60° C.within two minutes to a mixture of 60 g tert-butyl(trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylateand 37.5 g triphenylphosphine in 300 mL dioxane. The mixture is heatedto 80-90° C. for 100 min. After 20 min at 50-60° C., 84 mL of 4 Mhydrochloric acid in dioxane are added to the mixture and the mixture isstirred for 3 h at 50-85° C. After stirring for 17 h at ambienttemperature the mixture is cooled to 5° C. and the precipitate isfiltered off. The filter cake is washed with a 1:1 mixture ofdioxane/acetonitrile and with tert-butylmethylether. After drying at 50°C., 40 g of product is obtained.

Mass spectrum (ESI⁺): m/z=473 [M+H]⁺

Collection of Data

The following equipment and test conditions are used to collect the dataappended hereto.

X-ray Powder Diffractometer

STOE Stadi P X-ray powder diffractometer with a location-sensitivedetector in transmission mode with a curved germanium (111) primarymonochromator; wavelength used: CuK_(α) with λ=1.540598 Å; operation ofthe X-ray tube: 40 kV, 40 mA; 2 θ range: 3-40°. The complete X-raypowder diffraction pattern of compound (I) is shown in FIG. 1. Thecharacteristic peak positions for the X-ray powder diffraction patternof compound (I) is shown in Table 1 below:

TABLE 1 X-ray reflections to 30° 2 ⊖ inclusive intensities(standardised) of compound (I) 2 ⊖ d_(hkl) Intensity [°] [Å] I/I_(o) [%]5.76 15.34 5 6.20 14.25 12 10.00 8.84 11 10.65 8.30 22 11.52 7.68 1512.43 7.11 26 13.89 6.37 10 14.41 6.14 4 14.95 5.92 14 15.33 5.77 2715.68 5.65 8 16.10 5.50 10 16.61 5.33 15 17.09 5.18 14 18.06 4.91 1718.44 4.81 13 18.92 4.69 100 19.30 4.60 17 19.60 4.53 6 20.37 4.36 5120.70 4.29 6 21.38 4.15 26 22.41 3.96 17 23.06 3.85 49 23.64 3.76 1024.19 3.68 7 24.67 3.61 79 25.29 3.52 8 25.68 3.47 3 26.61 3.35 13 26.943.31 4 27.40 3.25 21 27.67 3.22 7 28.13 3.17 6 28.68 3.11 13 29.05 3.076 29.55 3.02 19 29.79 3.00 7Thermoanalysis Equipment

A DSC 822 made by Mettler Toledo is used. The following measuringparameters are used: heating rate: 10 K/min; type of crucible:perforated aluminium crucible; atmosphere: N₂, 80 ml/min flux; typicalweights: 3-10 mg.

A TGA/SDTA 851 made by Mettler Toledo which is coupled to a NicoletFT-IR 4700 spectrometer (for analysing the volatile fractions) is used.The following measuring parameters are used: heating rate: 10 K/min;type of crucible: open aluminium oxide crucible; atmosphere: N₂, 20ml/min flux; typical weights: 15-25 mg.

The melting point of compound (I) can be inferred from the DSC/TGschemes in FIG. 2 appended hereto.

Equipment for Water Sorption Tests

A DVS-1 made by Surface Measurement Systems (=SMS) is used to test thehygroscopic characteristics: the following humidity profiles are used:10-90% r.h. in 10% steps, recording both a sorption and a desorptionprofile, typical weights: 10-20 mg

The corresponding diagrams (kinetic and isothermic plot) of thedifferent forms are shown in FIGS. 3 a) and b).

Biological Test

The biological properties of compound (I) are investigated as follows,for example:

The inhibition of the EGF-R-mediated signal transmission can bedemonstrated e.g. with cells which express human EGF-R and whosesurvival and proliferation depend on stimulation by EGF or TGF-alpha. Amurine haematopoietic cell line is genetically modified so as to expressfunctional human EGF-R. The proliferation of this cell line cantherefore be stimulated by EGF.

The test is carried out as follows:

The cells are cultivated in RPMI/1640 medium. The proliferation isstimulated with 20 ng/ml of human EGF (Promega). To investigate theinhibitory activity of the compounds according to the invention thesecompounds are dissolved in 100% dimethylsulfoxide (DMSO) and added tothe cultures in various dilutions, the maximum DMSO concentration being1%. The cultures are incubated for 48 hours at 37° C.

In order to determine the inhibitory activity of compound (I) accordingto the invention the relative cell number is measured in O.D. unitsusing the Cell Titer 96™ AQueous NonRadioactive Cell Proliferation Assay(Promega). The relative cell number is calculated as a percentage of thecontrol and the concentration of active substance which inhibits theproliferation of the cells by 50% (IC50) is derived therefrom.

TABLE 2 Inhibition of the EGFR-dependent proliferation Compound IC₅₀[nM] (I) 4Indications

As has been found, the compound of formula (I) is characterized by itsversatility in the therapeutic field. Particular mention should be madeof the possible applications for which the compound of formula (I)according to the invention is preferably used on the basis of itspharmaceutical efficacy as a tyrosine inhibitor.

The compound of general formula (I) according to the invention thusinhibits signal transduction by tyrosine kinases, as demonstrated by theexample of the human EGF receptor, and is therefore useful for treatingpathophysiological processes caused by hyperf unction of tyrosinekinases. These are e.g. benign or malignant tumours, particularlytumours of epithelial and neuroepithelial origin, metastasisation andthe abnormal proliferation of vascular endothelial cells(neoangiogenesis).

The compound (I) according to the invention is also useful forpreventing and treating diseases of the airways and lungs which areaccompanied by increased or altered production of mucus caused bystimulation of tyrosine kinases, e.g. in inflammatory diseases of theairways such as chronic bronchitis, chronic obstructive bronchitis,asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis,cystic fibrosis, α1-antitrypsin deficiency, or coughs, pulmonaryemphysema, pulmonary fibrosis and hyperreactive airways.

The compound (I) is also suitable for treating diseases of thegastrointestinal tract and bile duct and gall bladder which areassociated with disrupted activity of the tyrosine kinases, such as maybe found e.g. in chronic inflammatory changes such as cholecystitis,Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinaltract or such as may occur in diseases of the gastrointestinal tractwhich are associated with increased secretions, such as Ménétrier'sdisease, secreting adenomas and protein loss syndrome.

In addition, the compound (I) may be used to treat other diseases causedby abnormal function of tyrosine kinases, such as e.g. epidermalhyperproliferation (psoriasis), benign prostatic hyperplasia (BPH),inflammatory processes, diseases of the immune system,hyperproliferation of haematopoietic cells, the treatment of nasalpolyps, etc.

Combinations

The compound of formula (I) may be used on its own or in combinationwith other active substances. These combinations may be administeredeither simultaneously or sequentially. Optionally the compound offormula (I) may also be used in combination with W, wherein W denotes apharmacologically active substance and is selected (for example) fromamong betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors,LTD4-receptor (CysLT1, CysLT2, CysLT3) antagonists, LTB4-receptor (BLT1,BLT2) antagonists, inhibitors of MAP kinases such as for example p38,ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, bradykinin (BK1, BK2) receptorantagonists, endothelin receptor antagonists, CXCR1 and/or CXCR2receptor antagonists, and anti-tussive substances.

In addition, double or triple combinations of W may be combined with thecompounds of formula (I). Examples of combinations of W with thecompound of formula (I) might be:

-   -   W denotes a betamimetic, combined with an anticholinergic,        corticosteroid, PDE4-ihibitor, EGFR-inhibitor or LTD4-receptor        antagonist,    -   W denotes an anticholinergic, combined with a betamimetic,        corticosteroid, PDE4-inhibitor, EGFR-inhibitor or LTD4-receptor        antagonist,    -   W denotes a corticosteroid, combined with a PDE4-inhibitor,        EGFR-inhibitor or LTD4-receptor antagonist    -   W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor or        LTD4-receptor antagonist    -   W denotes an EGFR-inhibitor, combined with an anticholinergic.

Examples of betamimetics which may be used here preferably includecompounds which are selected from among arformoterol, carmoterol,formoterol, indacaterol, salmeterol, albuterol, bambuterol, bitolterol,broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenalin, ibuterol,isoetharin, isoprenalin, levosalbutamol, mabuterol, meluadrin,metaproterenol, milveterol, orciprenalin, pirbuterol, procaterol,reproterol, rimiterol, ritodrin, salmefamol, soterenol, sulphonterol,terbutalin, tiaramid, tolubuterol, zinterol and6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxyphenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,N-(5-{2-[3-(4,4-diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,N-(5-{2-[3-(4,4-diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,N-(5-{2-[3-(4,4-diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,N-(5-{2-[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)methanesulphonamide,8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,N-[2-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide,8-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one,8-hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)ethyl]-1H-quinolin-2-one,5-[(1R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,[3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea,4-((1R)-2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol,3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,3-(3-{7-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulphonamide,4-((1R)-2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol,N-1-adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide,(1R)-5-{2-[6-(2,2-difluoro-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-hydroxy-1H-quinolin-2-one,(R,S)-4-(2-{[6-(2,2-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[6-(4,4-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one,(R,S)-[2-({6-[2,2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,4-(1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol,(R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5|5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol,(R,S)-[5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide,(R,S)-4-[2-({6-[2-(3-bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,(R,S)—N-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea,3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethyl)phenyl]imidazolidin-2,4-dione,(R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one,4-((1R)-2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[6-(3,3-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-(2-{[6-(2,2-difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol,3-[2-(3-chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide,N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-ylethoxy)-propionamide7-[2-(2-{3-[2-(2-chloro-phenyl)-ethylamino]-propylsulphanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazole-2-one,

optionally in the form of the racemates, enantiomers, diastereomers andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates or hydrates thereof. Preferably, according to theinvention, the acid addition salts of the betamimetics are selected fromamong hydrochloride, hydrobromide, hydriodide, hydrosulphate,hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

Examples of anticholinergics which may be used here preferably includecompounds which are selected from among: tiotropium salts, preferablythe bromide salt, oxitropium salts, preferably the bromide salt,flutropium salts, preferably the bromide salt, ipratropium salts,preferably the bromide salt, aclidinium salts, preferably the bromidesalt, glycopyrronium salts, preferably the bromide salt, trospium salts,preferably the chloride salt, tolterodine,(3R)-1-phenethyl-3-(9H-xanthen-9-carbonyloxy)-1-azoniabicyclo[2,2,2]octane-salts.In the above-mentioned salts the cations are the pharmacologicallyactive constituents. As X⁻ anions the above-mentioned salts maypreferably contain chloride, bromide, iodide, sulphate, phosphate,methanesulphonate, nitrate, maleate, acetate, citrate, fumarate,tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, whilechloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts thechlorides, bromides, iodides and methanesulphonates are particularlypreferred.

Other specified compounds are: tropenol 2,2-diphenylpropionatemethobromide, scopine 2,2-diphenylpropionate methobromide, scopine2-fluoro-2,2-diphenylacetate methobromide, tropenol2-fluoro-2,2-diphenylacetate methobromide, tropenol3,3′,4,4′-tetrafluorobenzilate methobromide, scopine3,3′,4,4′-tetrafluorobenzilate methobromide, tropenol4,4′-difluorobenzilate methobromide, scopine 4,4′-difluorobenzilatemethobromide, tropenol 3,3′-difluorobenzilate methobromide, scopine3,3′-difluorobenzilate methobromide; tropenol9-hydroxy-fluorene-9-carboxylate methobromide, tropenol9-fluoro-fluorene-9-carboxylate methobromide, scopine9-hydroxy-fluorene-9-carboxylate methobromide, scopine9-fluoro-fluorene-9-carboxylate methobromide; tropenol9-methyl-fluorene-9-carboxylate methobromide, scopine9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropinebenzilate methobromide, cyclopropyltropine 2,2-diphenylpropionatemethobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylatemethobromide, cyclopropyltropine methyl 4,4′-difluorobenzilatemethobromide, tropenol 9-hydroxy-xanthene-9-carboxylate methobromide,scopine 9-hydroxy-xanthene-9-carboxylate methobromide, tropenol9-methyl-xanthene-9-carboxylate-methobromide, scopine9-methyl-xanthene-9-carboxylate-methobromide, tropenol9-ethyl-xanthene-9-carboxylate methobromide, tropenol9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine9-hydroxymethyl-xanthene-9-carboxylate methobromide. The above-mentionedcompounds may also be used as salts within the scope of the presentinvention, while instead of the methobromide, the metho-X salts may beused wherein X may have the meanings given hereinbefore for X⁻.

Compounds which may be used as corticosteroids are preferably thoseselected from among: beclomethasone, betamethasone, budesonide,butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol,flunisolide, fluticasone, loteprednol, mometasone, prednisolone,prednisone, rofleponide, triamcinolone, tipredane andpregna-1,4-diene-3.20-dione,6-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-21-[[4-[(nitrooxy)methyl]benzoyl]oxy]-,(6-alpha,11-beta,16-alpha)-(9Cl) (NCX-1024),16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one(RPR-106541), (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,(S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-17-carbothionate,cyanomethyl6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives thereof,the solvates and/or hydrates thereof. Any reference to steroids includesa reference to any salts or derivatives, hydrates or solvates thereofwhich may exist. Examples of possible salts and derivatives of thesteroids may be: alkali metal salts, such as for example sodium orpotassium salts, sulphobenzoates, phosphates, isonicotinates, acetates,dichloroacetates, propionates, dihydrogen phosphates, palmitates,pivalates or furoates.

PDE4-inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram,oglemilast, tetomilast, and5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-quinoline(D-4418),N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)-quinoline(D-4396 (Sch-351591)),N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyoxylicacid amide (AWD-12-281 (GW-842470)),9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purin-6-amine(NCS-613),4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine(CDP-840),N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-4-pyridinecarboxamide(PD-168787),4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-pyridinone(T-440),2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-phthalazinone(T-2585),(3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine(V-11294A),beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide(CDC-801), imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one,9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888),5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl],(3S,5S)-2-piperidinone (HT-0712),4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)ethyl]-alpha,alpha-bis(trifluoromethyl)-benzenemethanol(L-826141),N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,(−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′—[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,

optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof. According to theinvention the preferred acid addition salts are selected from amonghydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,hydrobenzoate and hydro-p-toluenesulphonate.

LTB4-receptor antagonists used here are preferably compounds selectedfrom among for example amebulant (=ethyl[[4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]phenyl]iminomethyl]-carbamate),optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates, prodrugs or hydrates thereof. Accordingto the invention the preferred acid addition salts are selected fromamong hydrochloride, hydrobromide, hydriodide, hydrosulphate,hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

LTD4-receptor antagonists used here are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast, and(E)-8-[2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one(MEN-91507),4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid (MN-001),1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropaneaceticacid,1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneaceticacid,[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof. According to theinvention the preferred acid addition salts are selected from amonghydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,hydrobenzoate and hydro-p-toluenesulphonate.

By salts or derivatives which the LTD4-receptor antagonists areoptionally capable of forming are meant, for example: alkali metalsalts, such as for example sodium or potassium salts, alkaline earthmetal salts, sulphobenzoates, phosphates, isonicotinates, acetates,propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

MAP Kinase inhibitors used are preferably compounds selected from among:

bentamapimod (AS-602801), doramapimod (BIRB-796), 5-carbamoylindole(SD-169),6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridinecarboxamide(VX-702),alpha-[2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazoleacetonitrile(AS-601245),9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1.6]benzodiazocine-10-carboxylicacid (CEP-1347),4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1H-pyrazole-4-yl]-pyrimidine(SC-409),optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, prodrugs, solvates or hydrates thereof.

Bradykinin receptor antagonists that may be used are preferablycompounds selected from among icatibant and 1-piperazinepentanaminium,delta-amino-4-[[4-[[[2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl]sulphonyl]amino]tetrahydro-2H-pyran-4-yl]carbonyl]-N,N,N-trimethyl-ε-oxo,chloride, hydrochloride (1:1:1), (deltaS)-(MEN-16132), optionally in theform of the racemates, enantiomers and diastereomers thereof andoptionally in the form of the pharmacologically acceptable acid additionsalts, prodrugs, solvates or hydrates thereof.

Endothelin antagonists that may be used are preferably compoundsselected from among actelion-1, ambrisentan, sitaxsentan,N-(2-acetyl-4,6-dimethylphenyl)-3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulphonyl]-2-thiophenecarboxamide(TBC-3214) and bosentan, optionally in the form of the racemates,enantiomers and diastereomers thereof and optionally in the form of thepharmacologically acceptable acid addition salts, prodrugs, solvates orhydrates thereof.

Antitussive substances that may be used are preferably compoundsselected from among hydrocodone, caramiphen, carbetapentane anddextramethorphan, optionally in the form of the racemates, enantiomersand diastereomers thereof and optionally in the form of thepharmacologically acceptable acid addition salts, prodrugs, solvates orhydrates thereof.

Substances of preferred CXCR1 and/or CXCR2 receptor antagonists that maybe used are preferably compounds such as e.g.3-[[3-[(dimethylamino)carbonyl]-2-hydroxyphenyl]amino]-4-[[(R)-1-(5-methylfuran-2-yl)propyl]amino]cyclobut-3-ene-1,2-dione(SCH-527123),

optionally in the form of the racemates, enantiomers and diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, prodrugs, solvates or hydrates thereof.

It is preferable, according to the invention, to use the acid additionsalts of the above-mentioned betamimetics, anticholinergics,corticosteroids, PDE4 inhibitors, LTB4 (BLT1, BLT2) receptorantagonists, LTD4 (CysLT1, CysLT2, CysLT3) receptor antagonists,inhibitors of MAP kinases such as for example p38, ERK1, ERK2, JNK1,JNK2, JNK3 or SAP, bradykinin receptor antagonists, endothelin receptorantagonists, antitussive substances, CXCR1 and/or CXCR2 receptorantagonists also selected from among hydrochloride, hydrobromide,hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate.

Pharmaceutical Compositions

The compound according to the invention may be administered by oral,transdermal, inhalative, parenteral or sublingual route. The compoundaccording to the invention is present as an active ingredient inconventional preparations, for example in compositions consistingessentially of an inert pharmaceutical carrier and an effective dose ofthe active substance, such as for example tablets, coated tablets,capsules, wafers, powders, solutions, suspensions, emulsions, syrups,suppositories, transdermal systems etc. An effective dose of thecompound according to the invention for oral administration is between0.1 and 5000, preferably between 1 and 500, particularly preferablybetween 5-300 mg/dose, when administered by intravenous, subcutaneous orintramuscular route between 0.001 and 50, preferably between 0.1 and 10mg/dose. For Inhalation, according to the invention suitable solutionsare those that contain 0.01 to 1.0, preferably 0.1 to 0.5% of activesubstance. For inhalative administration the use of powders, ethanolicor aqueous solutions is preferred. It is also possible to use thecompound according to the invention as an infusion solution, preferablyin a physiological saline solution or nutrient solution.

The compound according to the invention may be used on its own or inconjunction with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances. Suitable formulations include, for example, tablets,capsules, suppositories, solutions, syrups, emulsions or dispersiblepowders. Corresponding tablets may be obtained for example by mixing theactive substance(s) with known excipients, for example inert diluents,such as calcium carbonate, calcium phosphate or lactose, disintegrantssuch as maize starch or alginic acid, binders such as starch orgelatine, lubricants such as magnesium stearate or talc and/or agentsfor delaying release, such as carboxymethyl cellulose, cellulose acetatephthalate, or polyvinyl acetate. The tablets may also comprise severallayers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g. with theaddition of preservatives such as p-hydroxybenzoates, or stabiliserssuch as alkali metal salts of ethylenediamine tetraacetic acid, andtransferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

For pharmaceutical use the compound according to the invention isgenerally used for warm-blooded vertebrates, particularly humans, indoses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. Foradministration it may be formulated for example with one or moreconventional inert carriers and/or diluents, e.g. with corn starch,lactose, glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, stearyl alcohol, carboxymethylcellulose or fatty substances suchas hard fat or suitable mixtures thereof to produce conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions, solutions, sprays or suppositories.

The Examples which follow illustrate the present invention withoutrestricting its scope:

Examples of Pharmaceutical Formulations

A) Coated tablets containing 75 mg of active substance Composition: 1tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mgcorn starch 35.5 mg polyvinylpyrrolidone 10.0 mghydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mgPreparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinyl-pyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Blanks 13 mm in diameter areproduced in a tablet-making machine and these are then rubbed through ascreen with a mesh size of 1.5 mm using a suitable machine and mixedwith the rest of the magnesium stearate. This granulate is compressed ina tablet-making machine to form tablets of the desired shape.

-   -   Weight of core: 230 mg    -   die: 9 mm, convex

The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose. The finished film-coatedtablets are polished with beeswax.

-   -   Weight of coated tablet: 245 mg.

B) Tablets containing 100 mg of active substance Composition: 1 tabletcontains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mgpolyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mgMethod of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

C) Tablets containing 150 mg of active substance Composition: 1 tabletcontains: active substance 150.0 mg powdered lactose 89.0 mg corn starch40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesiumstearate 1.0 mg 300.0 mgPreparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat

D) Hard gelatine capsules containing 150 mg of active substanceComposition: 1 capsule contains: active substance 150.0 mg corn starch(dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesiumstearate 3.0 mg approx. 420.0 mgPreparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

E) Suppositories containing 150 mg of active substance Composition: 1suppository contains: active substance 150.0 mg polyethyleneglycol 1500550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitanmonostearate 840.0 mg 2,000.0 mgPreparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

F) Suspension containing 50 mg of active substance Composition: 100 mlof suspension contain: active substance 1.00 gcarboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 gpropyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70%sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 mlPreparation:

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution and the flavouring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

-   -   5 ml of suspension contain 50 mg of active substance.

G) Ampoules containing 10 mg active substance Composition: activesubstance 10.0 mg 0.01N hydrochloric acid q.s. double-distilled water ad2.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

H) Ampoules containing 50 mg of active substance Composition: activesubstance 50.0 mg 0.0 N hydrochloric acid q.s. double-distilled water ad10.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

The invention claimed is:
 1. A method for the treatment of inflammatoryor allergic diseases of the airways comprising administering atherapeutically effective amount of the compound of formula (I),characterized in that reflections in the X-ray powder diagram occur atd_(hkl) values of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 Å,optionally in the form of a tautomer thereof, to a patient in needthereof


2. The method according to claim 1, wherein the inflammatory or allergicdisease of the airways is selected from chronic bronchitis, chronicobstructive bronchitis (COPD), asthma, bronchiectasis, allergic ornon-allergic rhinitis or sinusitis, cystic fibrosis, α1-antitrypsindeficiency, or coughs, pulmonary emphysema, pulmonary fibrosis andhyperreactive airways.